Multigene Kinase Network, Kidney Transport and Salt in Essential Hypertension

描述（由申请人提供）：原发性高血压是对公共卫生的主要威胁，影响世界上超过10亿人，每年造成500万人肾脏和心血管疾病死亡和发病。像其他复杂的疾病一样，具有变异等位基因的多种基因和不同的环境压力被认为是导致这种疾病的原因。使用全基因组关联策略，我们最近确定了第一个原发性高血压易感基因STK39（又名SPAK丝氨酸/苏氨酸激酶），阐明了一个新描述的多基因激酶网络和特定的环境触发因素-饮食盐-在高血压的发生中。本研究小组和其他研究人员的现有证据表明：1)STK39与WNK基因产物相互作用，丝氨酸/苏氨酸激酶在一种罕见的高血压和高钾血症家族疾病中发生突变，以控制肾盐排泄和维持血压；2)膳食钠和钾通过STK39/WNK通路不同地触发信号，调节关键肾盐转运蛋白噻嗪类利尿敏感氯化钠共转运蛋白（NCC）的活性；3) stk39信号的异常获得导致NCC活性的不适当增加，导致钠潴留和高血压。在这里，我们汇集了一个多学科的团队，开发和应用新的转基因动物模型和试剂，以我们最近的发现为基础，测试这些令人兴奋的关于高血压发展中基因-基因和基因-环境相互作用的新想法。这些新工具和知识的发展将揭示该病的潜在分子和遗传机制。它还将为研究和确定新的干预治疗策略提供急需的模型。

DESCRIPTION (provided by applicant): Essential hypertension is a major threat to public health, affecting over a billion people in the world and contributing to kidney and cardiovascular mortality and morbidity in 5 million people annually. Like other complex disorders, multiple genes with variant alleles and different environmental stresses are thought to contribute to the disease. Using a genome-wide association strategy, we recently identified the first essential hypertension susceptibility gene, STK39 (aka SPAK serine/threonine kinase), illuminating a newly described, multi-gene kinase network and a specific environmental trigger--dietary salt-- in the genesis of hypertension. Available evidence from our group and others suggests: 1) STK39 interacts with the products of the WNK genes, serine/threonine kinases that are mutated in a rare familial disorder of hypertension and hyperkalemia, to control kidney salt excretion and maintain blood pressure; 2) Dietary sodium and potassium differently trigger signaling through the STK39/WNK pathway to regulate the activity of a key renal salt transport protein, the thiazide diuretic sensitive sodium chloride co- transporter (NCC); 3) Aberrant gain-of-STK39 signaling causes an inappropriate increase in NCC activity, leading to sodium retention and hypertension. Here we bring together a mutlidisciplinary team to develop and apply novel transgenic animal models and reagents to test these exciting new ideas about gene-gene and gene-environment interactions in the development of hypertension, building on our recent discoveries. Development of these new tools and knowledge will shed light on the underlying molecular and genetic mechanisms of the disease. It also will provide much-needed models to study and identify new therapeutic strategies for intervention. PUBLIC HEALTH RELEVANCE: Essential hypertension is a major threat to public health, affecting over a billion people in the world and contributing to kidney and cardiovascular mortality and morbidity in 5 million people annually. Like other complex disorders, multiple genes with variant alleles and different environmental stresses are thought to contribute to the disease. Here we bring together a mutlidisciplinary team of experts in the field to develop and apply novel transgenic animal models and reagents to test exciting new ideas about a multi-kinase gene network and a specific environmental trigger--dietary salt--in the genesis of hypertension, building on our recent GWA discovery of STK39 kinase as an essential hypertension susceptibility gene.